Many neurons are silent until excited synaptically. In some circuits, including those of the cerebellum, however, it is becoming clear that individual neurons are intrinsically active, firing regular action potentials spontaneously, in the absence of synaptic input. In such neurons, rather than inducing or preventing action potentials, synaptic excitation or inhibition modulates the intrinsic firing pattern. The current proposal is motivated by the question of what constitutes signal and what constitutes noise in a system with spontaneously active elements. The goal is to explore the mechanisms underlying "effective" synaptic signals--i.e. , those that significantly modify postsynaptic firing--and ultimately to test the consequences of modulating or disrupting synaptic signals, either by plasticity or by pathophysiology. The proposed research focuses on synaptic transmission between Purkinje neurons and cerebellar nuclear neurons. Tissue will be used from 2-3 week old wild-type and ataxic mice. Experiments will be performed on cerebellar nuclear neurons either in acute isolation or in cerebellar slices in which synaptic contacts from Purkinje neurons are intact. Voltage-clamp and current-clamp recordings of inhibitory synaptic responses evoked by stimulation of Purkinje cell afferents, recordings of inhibitory neurotransmitter receptor kinetics, and histological studies will be used to examine the mechanisms underlying synaptic depression at the Purkinje-to-nuclear cell synapse. The resulting data will provide general information about the adaptive significance of spontaneously active elements in neural circuits, as well as specific information about cellular basis of information transfer in the functional and dysfunctional cerebellum. [unreadable] [unreadable] [unreadable]